PO1 SUMMARY / ABSTRACT Type 1 diabetes (T1D) is a disorder that arises following the autoimmune destruction of insulin producing pancreatic ?-cells. Previous studies, including nearly 250 peer reviewed articles supported by this P01 since its genesis some two decades ago, demonstrated that individuals with- or at increased-risk for T1D display a series of innate and adaptive immunological abnormalities, as well as genetic-based aberrancies, that were associated with disease susceptibility. These efforts have identified a variety of immune dysfunctions associated with T1D including but not limited to ?Interferonopathy? - defined as the elevated production of and response to Type 1 interferons, impaired function of regulatory T cells (Treg), and abnormal immune cell:cell interactions that not only drive autoimmunity in T1D but in addition, are strongly influenced by genetics (e.g., loss/gain of functional mutations, shifts in exon usage). Yet the contributions of T1D-risk loci to these processes remain quite unclear. Thus, our goal in seeking renewal of this P01 is to elucidate the mechanisms by which T1D-associated genes both generally (Projects 2 and 3) and specifically; IFIH1, TYK2 (Project 1), and IKZF4 (Project 3), impart functional immunoregulatory abnormalities (Project 2) that result in expansion of self-reactive adaptive immune cells, defective regulatory/effector mechanisms in T cells, inflammatory antigen presenting cells (APC), abnormal immune function in specific cell types, unusual patterns of lymphoid development, and inappropriate responses of ?-cells to danger/inflammatory signals. These activities will collectively test the P01's overall hypothesis that defects in genetic and immunologic pathways are key to engender the autoimmune destruction of pancreatic ?-cells that results in T1D. This P01 will examine this hypothesis through three separate but highly interactive Projects that (importantly) have a strong history of sharing data, using innovative technologies, and assess fresh and cryopreserved samples from well characterized human subjects with or at risk for T1D as ascertained through two Core facilities: Core A - Administrative Core and Core B - Laboratory Core. These proposed studies are further supported by the rich environment for T1D research at the University of Florida that includes resources such as pancreatic and lymphoid tissue samples from the Network for Pancreatic Organ donors with Diabetes Network (nPOD), interactions with major disease networks including the NIH Immune Tolerance Network and TrialNet, and special efforts related to the impact of race (as determined through highly active recruiting efforts) on the growing notion of T1D heterogeneity. The successes expected from the proposed studies should: 1) provide novel insights into the immune and genetic influences that contribute to T1D; 2) provide novel biomarkers for disease susceptibility and autoimmune activity associated with the disease, and could; 3) dramatically improve prospects for the development of an effective therapeutic capable of preventing and/or reversing T1D.